85 Systemic lupus erythematosus in Tunisian children: a case series

Abstract Background Childhood–onset systemic lupus erythematosus (c-SLE) is the prototype of a multisystem, inflammatory, heterogeneous autoimmune condition, characterized by simultaneous or sequential organ involvement. Compared with the adult-onset form, c-SLE have a worse prognosis. Objectives To review the epidemiological, and bio-clinical, characteristics of a c-SLE case series. Methods The files of patients diagnosed as c-SLE in the pediatrics department of Monastir, Tunisia from January 2004 to March 2022 were reviewed. Mean and standard-deviation were used to express normally-distributed variables, as verified by the Kolmogorov-Smirnov statistical test. Results Fourteen patients were collected. Female to male ratio was 6:1. Mean ages at lupus onset and diagnosis were 9.9 ± 1.4 years, [5–13.8 years] and 10.75 ± 2.3 years [6–14 years], respectively. Only two children had a family history of autoimmune disease. The initial admission was motivated primarily by skin and musculoskeletal manifestations, in 64.3% and 51.7% of cases, respectively. General signs (fever, asthenia) were observed in 35.7% of cases, hematological and gastrointestinal manifestations in 28.6% of cases each. In 3 cases, upper gastric endoscopy was performed prior to admission, in view of abdominal pain and vomiting. The physical examination noted various abnormalities. Malar rash (50%) and discoid lupus (28.6%) were the most frequent cutaneous manifestations, while skin biopsy was performed in three cases, all in keeping with lupus. The musculoskeletal manifestations were arthralgia (71.4%), arthritis and myositis (14.3%). Hematological manifestations included thrombocytopenia and leukopenia in 4 cases, as well as 3 cases of auto-immune hemolytic anaemia and splenomegaly. Renal manifestations were proteinuria in 7, haematuria in 6, and hypertension in 2 (with renal failure in one of the patients). The renal biopsy that was performed in one subject showed a class 2 lupus nephritis. Pleural effusion was observed in 3, pneumonia in 3, pericarditis in 2, myo-pericarditis in 1 and central nervous system (CNS) lupus in 1. Relevant results of the laboratory workup are illustrated in the following table:85 Table 1 Laboratory test Performed (%) Abnormal results (%) Erythrocyte sedimentation rate 14 (100%) 13 (92%) Antinuclear anti-bodies 14 (100%) 13 (92%) AntiDNA antibodies 7 (50%) 5 (71%) AntiSm antibodies 8 (57%) 5 (62%) Antiphospholipid antibodies 8 (57%) 5 (62%) Complement 11 (78%) 9 (81%) The formal diagnosis of SLE was established according to the ACR-1997 criteria in 7 cases (50%), the SLICC-2012 in 4 cases (28.6%) and EULAR/ACR-2019 in 3 cases (21.4%). The c-SLE diagnosis was associated with coeliac disease and Hashimoto thyroiditis in two of the subjects respectively. The therapeutic management was based on corticosteroids in 11 cases, hydroxychloroquine in 3, while cyclophosphamides and immunoglobulin were used for two subjects respectively. The outcomes were heterogeneous. Among 11 patients with sufficient follow-up, 6 cases of remission and 2 cases of relapse were noted. Major adverse events were not infrequent: one case each of cardiac tamponade, macrophage activation syndrome and severe CNS lupus were observed, all fatal. Conclusion Childhood–onset systemic lupus is a challenging disease, both to diagnose and to treat. The development of new criteria of higher specificity and sensitivity has greatly helped identify the incomplete types of lupus and allow for early-stage diagnosis, therefore preventing the serious complications of the disease.


Background
Wilson's disease (WD) is a rare, recessively inherited disorder of copper metabolism with its accumulation in multiple organs particularly in the liver and brain. Systematic lupus erythematosus (SLE) is an autoimmune disease like Wilson's disease, involves multiple organs and systems. The combination of Wilson's disease and systemic lupus erythematosus (SLE) is not usual apart from iatrogenism. Objectives we present a pediatric case of concurrent Wilson's disease and primary SLE not induced by penicillamine. After extensive research in the literature, this is the only male case described so far. The other seven cases reported are female. Case presentation A previously well 12-year-old boy was admitted to University Hospital Center of Batna (Algeria) with acute haemolysis (pallor, subictereus, and red urine). There was no consanguinity, or family history of note. Physical examination revealed normal development and growth, no fever, no lymphadenopathy, no hepatomegaly and splenomegaly. A complete blood count (CBC) revealed normochromic normocytic anaemia, thrombocytopenia, and leucopenia. His blood biochemistry showed hepatic cytolysis, and hepato-cellular insufficiency. Wilson's disease was suspected because of the combination of the impaired liver function, hemolytic anaemia, and normal alkaline phosphatase levels. Serum ceruloplasmin and copper levels were decreased, while urinary copper was elevated confirming the diagnosis of Wilson's disease. There was no neurological or ophthalmologic involvement. Family investigation revealed Wilson's disease with cirrhosis in a 9year-old brother. The onset of nephrotic syndrome and the presence of inflammatory syndrome cannot be explained by Wilson's disease. The kidney biopsy histopathology revealed nephritis lupus class II (WHO classification). Subsequent serum analysis also revealed positive native anti-DNA and anti-PCNA antibodies verified on a second sample. Based on all the findings, the final diagnosis for this patient was Wilson's disease combined with SLE. We started therapy with bolus of corticosteroids and Cyclophosphamide, relayed by Mycophenolate Moftil and hydroxychloroquine Cooper chelation has also been initiated. Improvement in renal and even hepatic damage was noted. Unfortunately, after two years, the patient presented abnormal movements with dysarthria. Brain MRI showed abnormal signals of the basal ganglia consistent with neurological damage in Wilson's disease. Discussion concomitant SLE and WD without penicillamine treatment is rare (7 cases reported in the literature with 3 children). To our knowledge, this is the first report of an association between Wilson's disease and SLE in male case. For our patient, SLE and Wilson's disease were diagnosed simultaneously as 4 described cases. Wilson's disease was first suspected due to unexplained impaired liver function with hemolytic anaemia. Copper Tests confirming the diagnosis. At that time, there was no neurological or ophthalmological impairment. For this patient, the worsening of the hematological involvement (pancytopenia) in an inflammatory context, with installation of a nephrotic syndrome cannot be explained by Wilson's disease. SLE was evoked despite the fact that it was a child and male. The PBR as well as the immunological workup were in favor of SLE disease. Treatment of SLE improved symptoms but later chelation could not prevent the usual neurologic complication of Wilson's disease at this age. The neurological involvement appeared at the age of 14 as described in the literature with the common sign dysathria, followed by the installation of abnormal movements due to the impairment of the basal ganglia objectived by MRI.

Conclusion
Wilson's disease and SLE not induced by penicillamine can co-exist. As there is no pathophysiological explanation, it's probably a simple fortuitous association.

Athul Kooliyath and Angela Migowa
The Aga Khan University, Nairobi

Background
Methotrexate is an antimetabolite commonly used as a chemotherapeutic and as a steroid sparing agent in multiple rheumatologic conditions. The common side effects are well documented and usually seen in patients receiving high dose therapy and hence more commonly seen in oncology. Here, we discuss a case on methotrexate toxicity in a patient being treated for Takayasu arteritis.

Methods
This was a retrospective case review Results A seventeen-year-old was seen in the rheumatology service with a diagnosis of Takayasu arteritis after being initially worked up due to hypertension. Methotrexate therapy was started at an initial dose of 25 mg to be taken weekly. She was later seen in the pediatric outpatient unit 10 days post initiation of therapy with a history of inability to feed due to oral sores and severe abdominal pain. She also complained of odynophagia and hence had poor oral intake. On further history, it was noted that the patient was taking the medication on a daily basis as opposed to the prescribed weekly regimen. On exam, she was noted to have extensive ulceration of her buccal mucosa, gingiva and tongue. She was also found to have severe epigastric tenderness. Her genital regions were however spared. A diagnosis of methotrexate toxicity was made and she was admitted to the high dependency unit for management. Methotrexate was immediately discontinued and a hyper hydration regimen was initiated with intravenous fluids (125 ml/m 2 /h). Her pain was managed with an intravenous morphine infusion. Particular care was taken to avoid drugs such as proton pump inhibitors (PPIs), non-steroidal antiinflammatory drugs (NSAIDs) and Sulphur containing drugs. A rescue was initiated with 15 mg/m 2 of folinic acid given 6 hourly. The patient made a full recovery and was discharged 4 days later.

Discussion and Conclusions
Methotrexate is a drug with varied and severe adverse effects. Toxicity with methotrexate affects multiple systems and can cause end organ damage. It is therefore of paramount importance to recognize toxicity early and manage appropriately before onset of end organ damage. The above patient was risk of hepatotoxicity, renal toxicity, Neurologic toxicity, methotrexate induced lung injury, hematologic toxicity and hypersensitivity. She developed mucositis as a result of the medication. Enhancing renal elimination of the drug is at the core of management. This can be done with hyperhydration, alkalinisation of urine and avoiding drugs that slow elimination of methotrexate such as PPIs, NSAIDs, tyrosine kinase inhibitors, sulfa drugs and penicillin like drugs. Once end organ damage is established, therapy is supportive and highly dependent on the organ systems involved and the extent of injury. It is necessary for clinicians to be well versed with the adverse effects expected with methotrexate as evidenced by this case for prompt diagnosis and sound management. It is also vital to counsel patients and parents about the medication-correct dosage and timing, expected adverse effects and when to seek medical attention. The initial admission was motivated primarily by skin and musculoskeletal manifestations, in 64.3% and 51.7% of cases, respectively. General signs (fever, asthenia) were observed in 35.7% of cases, hematological and gastrointestinal manifestations in 28.6% of cases each. In 3 cases, upper gastric endoscopy was performed prior to admission, in view of abdominal pain and vomiting. The physical examination noted various abnormalities. Malar rash (50%) and discoid lupus (28.6%) were the most frequent cutaneous manifestations, while skin biopsy was performed in three cases, all in keeping with lupus. The musculoskeletal manifestations were arthralgia (71.4%), arthritis and myositis (14.3%). Hematological manifestations included thrombocytopenia and leukopenia in 4 cases, as well as 3 cases of auto-immune hemolytic anaemia and splenomegaly. Renal manifestations were proteinuria in 7, haematuria in 6, and hypertension in 2 (with renal failure in one of the patients). The renal biopsy that was performed in one subject showed a class 2 lupus nephritis. Pleural effusion was observed in 3, pneumonia in 3, pericarditis in 2, myopericarditis in 1 and central nervous system (CNS) lupus in 1.
Relevant results of the laboratory workup are illustrated in the following table: 85 The formal diagnosis of SLE was established according to the ACR-1997 criteria in 7 cases (50%), the SLICC-2012 in 4 cases (28.6%) and EULAR/ACR-2019 in 3 cases (21.4%). The c-SLE diagnosis was associated with coeliac disease and Hashimoto thyroiditis in two of the subjects respectively. The therapeutic management was based on corticosteroids in 11 cases, hydroxychloroquine in 3, while cyclophosphamides and immunoglobulin were used for two subjects respectively. The outcomes were heterogeneous. Among 11 patients with sufficient follow-up, 6 cases of remission and 2 cases of relapse were noted. Major adverse events were not infrequent: one case each of cardiac tamponade, macrophage activation syndrome and severe CNS lupus were observed, all fatal.

Conclusion
Childhood-onset systemic lupus is a challenging disease, both to diagnose and to treat. The development of new criteria of higher specificity and sensitivity has greatly helped identify the incomplete types of lupus and allow for early-stage diagnosis, therefore preventing the serious complications of the disease.

Introduction
Hurler syndrome is the most severe form of mucopolysaccharidosis type I (MPS I), It is a hereditary, metabolic disorder due to an enzymatic deficiency in alpha-Liduronidase with tissue accumulation of glycosaminoglycans (GAGs) leading gradually to chronic multiple visceral dysfunction. We report three cases of multiple dysostosis in Hurler's disease. Case 1: Mr S.O, 26 years old man, presenting a dysmorphic syndrome associating short stature, facial dysmorphism, dental staining, gingival retractions, recurrent bronchial infections, mitral valve disease and joint deformities with a tunnel syndrome. Alpha L iduronidase dosage was performed confirming the diagnosis of Hurler's disease. The radiological assessment showed thickening of the cranial vault with poorly developed paranasal sinuses. Vertebral bodies collapse with oval shape, thoracolumbar kyphosis, hypoplasia of the iliac bones and the superior acetabular region, coxa-valga, with dysplastic femoral heads; cortical thinning of the long bones with a tapered appearance of the distal portions of the radius and ulna, small and deformed carpal bones, thin metacarpal bones, and dysplastic interphalangeal joints. Case 2: Patient B.M 17 years old girl, born of a consanguineous marriage, presenting with a malformation syndrome with short stature, facial dysmorphism, umbilical hernia, valvular heart disease, hepatomegaly, joint stiffness and deformity. Standard x-rays revealed macrocephaly with thickening of the cranial vault, flattened mandibular condyles, with hypertrophy of the clinoid processes; pectus excavatum, platyspondyly with thoracolumbar kyphoscoliosis, small and narrowed pelvis, enlarged and obliquus cotyles, coxa-valga with dysplastic femoral heads; long curved bones with metaphyseal and diaphyseal enlargement, short and enlarged proximal and intermediate phalanx and hypoplastic distal phalanx. Case 3: Patient D.W, 31-year-old female, born of a consanguineous marriage. The patient's physical examination shows a dysmorphic syndrome with short stature, facial dysmorphism, corneal opacity, recurrent otorhinolaryngological and bronchial infections, joint deformities with carpal tunnel syndrome. An alpha L iduronidase assay was performed confirming the diagnosis. The radiological assessment revealed macrocephaly, thickening of the cranial vault, an elongated J-shaped sella turcica, a short thorax, short and thick clavicles, widened, oarshaped ribs tapering at their vertebral insertion, ''spur'' vertebrae, thoracolumbar kyphoscoliosis, narrowed pelvis with coxa-valga and genu valgum, small and deformed carpal and tarsal bones with cortical thinning of long bones.

Discussion
The term dysostosis multiplex is used to describe skeletal abnormalities seen in MPS I that are often early and prominent. The progressive accumulation of GAGs led to an increase in chondrocyte apoptosis favoring the production of pro-inflammatory cytokines (TNFa, IL-1), chemokines and metalloproteases. This results in a degradation of the cartilaginous matrix, increased by the mechanical stresses, the disturbance of endochondral ossification, particularly in the sites subjected to articular mechanical stresses. That could explain the focal defect of the ossification of certain cartilaginous sites leading to this multiple dysplasia. At the axial level, the vertebrae can be oval shaped and flattened (platyspondyly). In the lower limbs, coxo-femoral abnormalities (coxa valga, splayed or flattened acetabulum), epiphyseal alterations, genu valgum, and hypoplasia of the iliac bones can be found. The metacarpal bones take on a tapered appearance like sucked candy cane and the interphalangeal joints of the hands and feet are dysplastic. Hypoplasia of the odontoid process leads to potentially serious cervical instability. Regular monitoring by MRI is necessary to avoid the risk of spinal cord section. The early introduction of enzyme replacement therapy led to a slower progression of symptoms, with improved growth, joint mobility and physical capacity, and stability over time, especially when associated with an appropriate rehabilitation care.

Conclusion
Even if Hurler syndrome is rare, it is still underdiagnosed, it can give various and varied clinico-radiographic features and potentially severe disabilities. Early diagnosis is essential since enzyme replacement therapy could stop or slow down the evolution to irreversible tissue damage.

Introduction
Behç et's disease is a chronic, relapsing, multisystem vasculitis. The diagnosis is essentially clinical, due to the absence of specific biological criteria, which remains very difficult to establish in pediatric age because of often insidious or atypical disease onset. The association of Pseudo Inflammatory Non-Specific Tumors (PTINS)